Targeting immune checkpoint B7-H6 in cancer immunotherapy

Abstract

Natural killer (NK) cells are central mediators of antitumor immunity and possess the unique ability to recognize and eliminate malignant cells independently of major histocompatibility complex (MHC) restriction. Compared with T-cell-based approaches, NK-cell immunotherapies generally exhibit a more favorable safety profile, highlighting their growing therapeutic potential in oncology. Among the ligands that regulate NK-cell activity, B7-H6 has emerged as a particularly attractive target because of its highly restricted expression in normal tissues and frequent upregulation across diverse malignancies. Initially identified as a ligand for the activating NK-cell receptor NKp30, B7-H6 is now recognized as a multifunctional molecule with roles extending beyond immune recognition. Accumulating preclinical evidence suggests that B7-H6 may contribute to tumor progression by regulating signaling pathways involved in proliferation, survival, migration, invasion, and immune evasion. Furthermore, the existence of soluble B7-H6 adds an additional layer of biological complexity and may influence both NK-cell function and therapeutic responsiveness. In this review, we summarize current knowledge regarding the regulation, expression patterns, and biological functions of B7-H6, with particular emphasis on its dual roles in tumor immunology and cancer cell biology. We discuss the emerging significance of soluble B7-H6, evaluate the current landscape of B7-H6-targeted therapeutic strategies, including bispecific engagers and cellular immunotherapies, and highlight key translational challenges that may influence clinical development. Collectively, current findings position B7-H6 as a promising immuno-oncologic target at the intersection of immune surveillance, immune escape, and malignant progression, warranting continued investigation as a next-generation therapeutic axis in cancer immunotherapy.